PROJECT SUMMARY MICROBIOME CORE The microbiome is a critical factor in educating both systemic as well as local immunity. Compartmentalized immune interactions with the resident flora have been identified at barrier tissues of the body, including the skin, gut, and lung. Each of these niches has different microbes and microbial community characteristics, which in turn uniquely shape and maintain innate and adaptive responses. In the lung, host immune responses to pathogen colonization?whether bacterial, fungal, or viral?are highly influenced by the local microbiota. A central hypothesis of this center is that the activity and specificity of the lung immune response can be amplified or diminished based on microbial configurations. Thus, to understand the milieu and activity of tissue-resident lung cells, including macrophages, lung dendritic cells, and lymphocytes, we must investigate the composition and functional interactions of the local microbiome with the host tissue. The central goal of the Microbiome Core is to enable discovery of mechanisms by which the microbiome influences lung immune function, as per the goals of The Jackson Laboratory Cooperative Center on Human Immunology (JAX CCHI). The Microbiome Core will be closely integrated with the Sample Core, providing sequence data, microbial cultivars, and computational analyses for both Research Projects and the Technology Development project. The Microbiome Core provides unique experimental and computational infrastructures that are not available as commodity services within or outside of The Jackson Laboratory. Key innovations that the Core brings to the JAX CCHI include: state-of-the-art metagenomic shotgun sequencing technologies and analyses at species- and strain-resolution; functional reconstructions; associative analyses with immune phenotypes; low-cost, microfluidics-based microbial isolate genome extraction; and MALDI (Matrix Assisted Laser Desorption/Ionization) technology for rapid assessment of strain identity and diversity. The application of these technologies to the goals of the JAX CCHI will be organized around three Specific Aims: AIM 1. Reconstruct microbial community composition from clinical samples at high resolution. AIM 2. Systematic cultivation of microbiota. AIM 3. Computational prediction of microbiome-immune interactions. Impact: The Core?s experimental and computational infrastructure will provide both the associative and mechanistic underpinnings for the CCHI?s central goals of understanding how the microbiome may modulate the lung?s immune response to viral perturbation.